Regulation of the Native Protein Landscape by Molecular Chaperones

ABSTRACT Cell homeostasis relies on dynamic and effective protein pathways. Typically, cooperative interactions between partner factors drives selectivity, yet the inherent stability of such complexes can be a detrimental to cell function. Adding to the complexity is the nature of the cell interior, which is densely packed with biological molecules with each having multiple, potential binding partners. As these features challenge the effectiveness of biological pathways by increasing the occurrence of off- pathway or non-productive interactions, cell must have mechanisms to counter these challenges. We believe molecular chaperones, in part, help resolve these complexities. Specifically, we suggest that the Hsp90 molecular chaperone system has evolved to recognize select intrinsically disorder regions (IDRs) on native proteins to both recognize client polypeptides and regulate their actions. Furthermore, we believe a breakdown in the Hsp90 network results in a deterioration of numerous cellular pathways and a triggering of premature aging.